Overuse of antibiotics in the last century has led to a rise in bacterial resistance, leading to many bacterial infections that are no longer treatable with current antibiotics. In the United States each year, 2.8 million people are diagnosed with a bacterial infection that is resistant to one or more antibiotics, and 35,000 people die due to the resistant infection according to the Centers for Disease Control and Prevention.

“One method of combatting antibiotic resistance is using a combination drug/inhibitor therapy,” said Caitlyn Thomas, a Ph.D. candidate in chemistry, presenting author on the study. An example of this type of therapy is Augmentin, a prescription antibiotic used to treat bacterial infections of the respiratory tract, which is composed of the antibiotic amoxicillin and the inhibitor clavulanic acid. Clavulanic acid inactivates a key protein that the bacterium uses to become resistant to amoxicillin. With the bacterial protein inactivated, the antibiotic — amoxicillin — is left to kill the bacteria, thereby treating the infection.

Before any new inhibitor can be used in the clinic, scientists need to have a complete understanding of how the inhibitor works. In the current study, Thomas and her team studied a bacterial protein called metallo-beta-lactamase, which renders many clinical strains of bacteria resistant to all penicillin-like antibiotics. Penicillin-like antibiotics make up over 60% of the entire antibiotic arsenal that is available to treat bacterial infections.

While many research labs throughout the world are attempting to create new inhibitors that inactivate metallo-beta-lactamases, Thomas and collaborators instead analyze how these new inhibitors work. “Because metallo-beta-lactamases contain two metal ions we are able to use a variety of spectroscopic techniques to study them,” said Thomas. “These experiments give us more insight into how to inhibitor behaves and whether it could potentially be a candidate for clinical use in the future.”

Hundreds of potential inhibitors have been reported in the literature, and several patents have been filed dealing with metallo-beta-lactamase inhibitors. Some of the reported inhibitors work by removing a required component of the metallo-beta-lactamase. These same inhibitors may remove this same required component of other proteins in humans, causing serious side effects. Other inhibitors bind directly to the metallo-beta-lactamase and inactivate the protein; inhibitors of this type are optimal for any new inhibitor that could be used in the clinic.

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Materials provided by American Society for Microbiology. Note: Content may be edited for style and length.

In pulmonary TB, the most common form of active TB disease, the Mycobacterium tuberculosis bacteria causes the formation of sites of high bacterial load, known as cavities. These cavities are poorly penetrated by TB drugs. After TB treatment is complete, there is likely to be tissue damage within the lungs that can lead to further lung problems such as permanent respiratory dysfunction leading to difficulty in breathing, stiffness in the lungs and bronchiectasis, which can make people cough up blood.

Researchers from NUS Yong Loo Lin School of Medicine’s Infectious Diseases Translational Research Programme have discovered that the use of a common antibiotic, doxycycline, in combination with TB drug treatment, reduces the size of lung cavities and accelerates markers of lung recovery.

In the Phase 2 double-blind trial conducted at the National University Hospital and TB Control Unit, the treatment was found to be safe, with side effects similar to patients on placebo pills. The study shows promise in delivering a new standard-of-care which can potentially prevent long term complications and the study team is seeking funds for a fully-powered larger scale Phase 3 trial to verify these findings.

“Pulmonary TB patients tend to suffer from lung damage after TB, which is associated with mortality, and poorer quality of life. Doxycycline is a cheap and widely available antibiotic that can decrease lung damage, and potentially improve quality of life for these patients,” said Assistant Professor Catherine Ong, Principal Investigator of the study and member of the Infectious Diseases Translational Research Programme (TRP) at NUS Medicine. The study findings were published in the Journal of Clinical Investigation.

Professor Paul Tambyah, who was also involved in the study and is Deputy Director of the Infectious Diseases TRP commented, “While we have been able to successfully treat most cases of TB for the last few decades, we have seen many people suffer the complications of the lung damage from the original TB infection. If this common drug, doxycycline, can help prevent the complications of “Long TB” (to use a term currently in vogue), this will really help a lot of patients in Singapore and worldwide.”

The Infectious Diseases TRP aims to provide a holistic, patient-centric approach to infectious diseases that are relevant to Singapore and the region. The Programme focuses on programmatic research areas including pathogen evolution and transmission, host-microbe interactions and vaccine and therapeutics development.

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Materials provided by National University of Singapore, Yong Loo Lin School of Medicine. Note: Content may be edited for style and length.

Microtubules are dynamic filaments that constantly grow and shrink again and, in this way, are responsible for many important processes in cells. The research team observed that intermediate filaments stabilise microtubules: when intermediate filaments are added to microtubules, shrinkage is suppressed and thus the lifespan of the microtubules is extended. To investigate whether this is actually due to direct interactions between the two filaments, a single microtubule was positioned crossed with a single intermediate filament.

Dr Laura Schaedel, who shares first authorship of the publication with Charlotta Lorenz (PhD student at the Institute for X-ray Physics at the University of Göttingen), explains: “The intermediate filament was ‘pulled’ over the microtubule like a bow over a violin string.” Lorenz adds, “This allows the two filaments to bind to each other. However, this bond is broken again shortly afterwards due to the pulling. The process of ‘tearing apart’ provides information about the strength of the bond.” Professor Stefan Klumpp from the Institute for the Dynamics of Complex Systems at Göttingen University, who led the project together with Professor Sarah Köster from the Institute for X-ray Physics, says, “In addition, we used models and simulations to show that the direct interaction leads to stabilisation.” The stabilisation of dynamic microtubules can be an important issue for biological cells, for example to regulate their local stability. “The interactions that we observed are important because they enable better understanding of cellular processes,” says Köster.

These results are in turn relevant for understanding many other processes, such as those involved in diseased cells. The new method to take direct measurements of the actual interaction of two different biopolymers can also be applied to other protein filaments, as well as to non-biological fibres.

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The findings shed light on how the hippocampus contributes to memory and exploration, potentially leading to therapies that restore hippocampal function, which is impacted in memory-related aging and neurodegenerative diseases such as dementia, the study authors said.

In the study, scientists monitored participants’ brain activity and tracked their eye movements while looking at different complex pictures. The scientists discovered that as we visually scan our environment and absorb new information, our hippocampus becomes activated, using short-term memory to better process new visual information to help us rapidly reevaluate situations.

How our memory helps us scan new environments

Imagine walking down the street and noticing an awkwardly parked car on your neighbor’s lawn. Maybe you quickly dismiss it and move on. But when you see an ambulance and fire truck approaching your location, you connect the dots and look back to see the scene of an accident. By using short-term memory to guide where you look, the hippocampus allows you to reexamine the car and form a lasting memory of the accident.

“At any given moment, your brain rapidly initiates eye movements that you are typically unaware of,” said corresponding author James Kragel, a postdoctoral research fellow at Northwestern University Feinberg School of Medicine. “Our findings suggest the hippocampus uses memory to inform where your eyes look, thereby priming the visual system to learn and reevaluate our environment on the fly.

“If you didn’t look back and see the crash, you might not encode that important information, but in using short-term memory retrieval, you can tie those clues together and remember details that cue bigger memories. It all comes down to building connections among these disparate elements that allow you to remember them later in a much easier way.”

The study will be published June 18 in the journal Science Advances.

“These findings emphasize that although hippocampal-dependent memory is typically considered a thing of the past, in fact, it operates in the moment to optimize our behavior and decision-making,” said senior study author Joel Voss, associate professor of medical social sciences, neurology, and psychiatry and behavioral sciences at Feinberg. “This is key to understanding hippocampal function and developing effective treatments for memory disorders.”

“It is as if you are using your memory to plan for what to expect, and then when it mismatches with what is actually unfolding, your hippocampus gets activated to reevaluate and update your current perception of what is going on,” Kragel said.

Tracking eye movements to learn more about memory

The study was conducted on patients with epilepsy who were undergoing neurosurgical monitoring at Northwestern Memorial Hospital to localize the source of their seizures. They had electrodes implanted in their brains to map seizure-related brain activity. During their stay in the epilepsy-monitoring unit, participants performed a memory task in which they studied lists of complex scenes with multiple people and objects (e.g. someone sitting at a park bench with food on the table, things happening in the background) followed by a memory test.

During the test, the participants indicated whether a presented scene was old or new. Throughout the task, the authors simultaneously recorded eye movements and neural activity to link hippocampal activity to memory-guided behaviors.

When studying a scene for the first time, participants often returned their gaze to a location they had just viewed hundreds of milliseconds prior. These “revisitation” eye movements enhanced spatiotemporal memory for scenes (remembering where an object was located or the sequence in which something happened). Brain recordings revealed the brain networks involved in generating these “revisitations,” as hippocampal activity shifted just before their execution. Increases in brain activity followed revisitations, which Kragel believes may form a lasting memory of the scene and its elements.

“This shows that the hippocampal contribution to memory unfolds over just hundreds of milliseconds during ongoing behavior, which is surprising given that the timecourse of its involvement, typically seen in long-term memory retrieval, is usually thought to be days to years,” Voss said.

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Materials provided by Northwestern University. Original written by Kristin Samuelson. Note: Content may be edited for style and length.

Michael Dillon, an associate professor in the University of Wyoming Department of Zoology and Physiology, was part of a research group that examined animals’ ability to respond to climate change likely depends on how well they modify their habitats, such as nests and burrows.

So, how are these animals doing? Are they succeeding, struggling, or are their efforts a mixed bag in adapting their habitats to climate change?

“One of the key reasons that we wrote this paper is that we don’t know the answer to this very important question!,” Dillon says. “We hope the paper will encourage scientists to begin answering this question.”

Dillon is a co-author of a paper, titled “Extended Phenotypes: Buffers or Amplifiers of Climate Change?,” that was published June 16 in Trends in Ecology & Evolution. The journal publishes commissioned, peer-reviewed articles in all areas of ecology and evolutionary science.

The lead author of the paper is Arthur Woods, a professor of biological sciences at the University of Montana. Other contributors to the paper were from the University of Tours in Tours, France; and Stellenbosch University in Stellenbosch, South Africa.

The study investigated extended phenotypes, which are modifications that organisms — birds, insects and mammals — make to their habitats.

“An extended phenotype can range from simply a hole in the ground occupied by an animal to leaves rolled into cavities by insects, to nests of all shapes and sizes built by birds and mammals, to termite mounds and bee colonies,” Dillon says.

Extended phenotypes are important because they filter climate into local sets of conditions immediately around the organism. This is what biologists call the microclimate.

Because extended phenotypes are constructed structures, they often are modified in response to local climate variation and, potentially, in response to climate change. This process is called plasticity of the extended phenotype.

“One example might be a bird nest that is well insulated to protect eggs or young birds from cold. As climates warm, if the bird does not adjust insulation in the nest, it may, in fact, cause the young to overheat,” Dillon explains.

In another prime example, termites build mounds that capture wind and solar energy to drive airflow through the colony, which stabilizes temperature, relative humidity and oxygen levels experienced by the colony.

However, the idea of microclimates is broader than constructed habitats. Microclimates typically differ substantially from nearby climates, which means that the climate in an area may provide little information about what animals experience in their microhabitats.

As an analogy, although a weather station might tell the public that the temperature in Laramie is 90 degrees Fahrenheit, simply by moving from the south to the north side of a building, one can experience microclimates that are strikingly different and often not captured by the weather data, Dillon says.

The same is true of animals of many different sizes. For example, a moose can move from an open sagebrush landscape to a shaded river corridor to cool off; a snake can move from its underground hole to a sunny rock to warm up; and a tiny insect shuttling between the top and bottom of a leaf can experience temperature differences of more than 20 degrees Fahrenheit.

“So, animals use microclimates, both by simply moving but also by building structures, such as nests, burrows, mounds and mines,” Dillon says.

Across the globe, rising levels of carbon dioxide in the Earth’s atmosphere are causing temperatures to rise and precipitation patterns to shift. For biologists, a key problem is to understand current effects of climate change on species, and to predict future effects, including how species’ ranges may shift and what the relative risks of extinction are for different animal species’ groups.

The research team favors a renewed effort to understand how extended phenotypes mediate how organisms experience climate change.

“We need a much better understanding of the basic biophysical principles by which extended phenotypes alter local conditions,” says Sylvain Pincebourde, an ecologist in the Insect Biology Research Institute at the University of Tours and one of the paper’s co-authors.

Another key challenge is to understand how much plasticity there is in extended phenotypes, and how much and how rapidly they can evolve.

“At this point, we pretty much have no idea,” Dillon says. “Can structures that buffer temperature variability keep up with the pace of climate change?”

We have two eyes, but perceive the tree in front of us only once. Our brain therefore has the complicated task of combining the information of both eyes in a meaningful way. To do so, visual stimuli first travel from the retina via so-called ganglion cells to the visual thalamus. There, the information does end up in clearly defined areas — depending on the type and eye-of-origin of retinal ganglion cells transporting the visual stimuli. Signals from the right and left eye are thus clearly separated in the visual thalamus and independently transmitted to the visual cortex. Only in this brain region, the incoming information is combined — at least according to a long-standing theory.

However, recent anatomical studies describe that a surprising number of neurons in the mouse visual thalamus has contact to both eyes. Does the separation of ‘left eye’ and ‘right eye’ information channels not hold true in mice? Scientists from Tobias Bonhoeffer’s department wanted to shed more light on this newly raised question. They further developed an optogenetic method, so that they could activate ganglion cells of both eyes successively with light of different colors and measure the corresponding electrical responses in a thalamic cell.

This analysis shows that indeed a multitude of neurons in the visual thalamus receive input from both retinas. But interestingly, there are only very few cells in which the signal strengths of both eyes are similar. In most cells, one eye dominates with a much higher input strength. The weak signals from the non-dominant eye did not trigger an action potential in the experiment and thus seem to not play a major role in the processing of visual information. “With these results, we can explain the contradictory findings of previous research,” says Tobias Rose, who led the study. “The neurons in the visual thalamus do form connections with both eyes, but are functionally monocular or, so to speak, one-eyed. That means that only the signal strength of one eye is high enough for the cells to respond.”

Selection of input

The spatial arrangement of retinal and thalamic cells and the resulting connection possibilities alone cannot explain the functional monocularity. Instead, the scientists showed that even with equal access to both eyes, thalamic cells establish functional connections with only one eye. Accordingly, there is a clear selection of the input source. In addition, the contact sites with the dominant eye seem to strengthen, while those of the non-dominant eye remain in an immature state.

Future studies aim to reveal how the dominant eye is determined and whether this mechanism also applies to different retinal ganglion cell types. Another interesting research topic are the immature contact sites. At first glance without obvious function, the question arises whether they could be activated when needed — and thus play a role, for example in amblyopia, a form of visual impairment.

With their study, the researchers prove that the mouse visual thalamus indeed transfers visual information in separate channels — presumably similar to humans. In addition, it becomes clear that anatomical data sets may be interpreted with caution: Just because neurons are in contact with each other does not mean that they communicate extensively.

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Materials provided by Max-Planck-Gesellschaft. Note: Content may be edited for style and length.